Clinical Trial Based Rationale for the Successful Use of DOAC in the Treatment of Cerebral Venous Sinus Thrombosis (CVST): A Case Report.

In cerebral venous sinus thrombosis (CVST), venous sinus occlusion increases venous pressure and disrupts venous return, resulting in progression to venous infarction and venous hemorrhage, with poor neurologic outcome. Therefore, early recanalization of the major venous sinus is critical. Anticoagulant therapy with continuous intravenous infusion of heparin and subsequent oral anticoagulant administration is the recommended first line of treatment for CVST. Some large clinical trials for venous thromboembolism (VTE) have shown that direct oral anticoagulant (DOAC) is non-inferior to the standard therapy with heparin or warfarin and causes less bleeding. In contrast, there are only a few reports on CVST treatment with DOAC such as Dabigatran, Rivaroxaban and Edoxaban describing good efficacy and safety. And there is one randomized clinical trial on DOAC treatment for CVST after acute phase. We report a successfully treated case of CVST in acute phase with progressive neurologic symptoms that achieved early recanalization of the obstructed sinus by an early switch from continuous intravenous infusion of heparin to oral Edoxaban.

Fatal Hemorrhage Immediately after Transvenous Embolization of Transverse-sigmoid Sinus Dural Arteriovenous Fistulas: A Case Report.

Objective: We report a case of intracerebral hemorrhage following emergency transvenous embolization for an acute symptomatic non-hemorrhagic dural arteriovenous fistula (dAVF). Case Presentation: An 83-year-old woman demonstrated gait disorder and disturbance of consciousness. A transverse-sigmoid dAVF with retrograde deep venous drainage was detected on DSA. The left sigmoid sinus-jugular vein and the sinus confluence were occluded and the dAVF drains via the straight sinus (SS), medial superior cerebral veins and deep veins to the superior sagittal sinus (SSS). The dAVF was emergently treated by sinus packing of the transverse-sigmoid sinus with coils with contralateral approach via the occluded sinus confluence. Although the dAVF was markedly regressed, massive cerebral hemorrhage developed in the left parietal lobe immediately after embolization. Conclusion: Although early treatment is required for dAVFs with aggressive symptoms, precious evaluation of their hemodynamics, particularly for drainage pattern, is mandatory to avoid a serious complication.

Intentional Herniation Technique with the Neuroform EZ Stent System for Preservation of Aneurysmal Neck Branch: A Case Report.

Endovascular treatment of bifurcation aneurysms is difficult and complicated because arterial branches may arise from the aneurysmal neck. We treat these cases with complex techniques such as Y or T stenting. In this report, we deployed one Neuroform EZ stent using the intentional herniation technique for the preservation of arterial branches. A 78-year-old female presented with two unruptured aneurysms. One was an 8 mm aneurysm located at the bifurcation of the internal carotid artery and the posterior communicating artery (PcomA). The other was an 11 mm aneurysm located at the cavernous segment of the internal carotid artery. A 4.5x20 mm Neuroform EZ stent was placed across the aneurysm neck. The delivery wire and microcatheter were pushed during deployment, similar to braided stents. High resolution cone beam computed tomography (CT) after stenting revealed the stent strut to be vertically aligned near the aneurysmal sac, and the PcomA orifice was preserved. We performed coil embolization easily and achieved acceptable obliteration. Our intentional herniation technique may be useful in some cases. Open cell stents have some advantages depending on the method of deployment.

Therapeutic strategy for pineal parenchymal tumor of intermediate differentiation (PPTID): case report of PPTID with malignant transformation to pineocytoma with leptomeningeal dissemination 6 years after surgery.

Pineal parenchymal tumor of intermediate differentiation (PPTID) is rare. The WHO first classified PPTID in 2000 as a pineal parenchymal tumor (PPT) with an intermediate prognosis between pineocytoma (PC) and pineoblastoma (PB). It is considered an intermediate-grade tumor and divided into WHO grade II or III.The number of available reports about PPTID is presently limited, and the appropriate management for this tumor has not yet been determined.The authors report a rare case of PC in a 63-year-old woman who presented with lower-extremity weakness and gait disturbance. A pineal mass lesion was detected on MRI. A diagnosis of PC was established after microsurgical gross-total tumor resection, and the patient received no adjuvant therapy after surgery. Two years after surgery, a partial recurrence was recognized and Gamma Knife radiosurgery was performed. Fours years later, the patient developed diffuse leptomeningeal dissemination. She was successfully treated with craniospinal irradiation. Leptomeningeal dissemination may develop 6 years after the initial diagnosis of PC. A histopathological study of the recurrent tumor revealed a malignant change from PC to PPTID.The present case shows the importance of long-term follow-up of patients with PPTs following resection and the efficacy of craniospinal irradiation in the treatment of leptomeningeal dissemination.

Utility of relative ADC ratio in patient selection for endovascular revascularization of large vessel occlusion.

PURPOSE: The relative apparent diffusion coefficient (ADC) ratio on magnetic resonance imaging (MRI) can be used to evaluate the degree of ischemia. Here, we assessed the predictability of ischemic reversibility and the risk of hemorrhagic transformation using the relative ADC ratio. METHODS: This single-center retrospective study analyzed 56 patients with acute occlusion of the internal carotid artery (ICA) or the middle cerebral artery (M1) with endovascular revascularization. Diffusion-weighted imaging (DWI) lesions were classified as reversible lesions, final infarct lesions, and hemorrhagic or non-hemorrhagic regions. The relative ADC ratio was calculated in each DWI lesion and was defined as the ratio of ADC pixel values within affected territory to ADC pixel values in contralateral normal brain regions. RESULTS: The average relative ADC ratio was 0.890±0.045 in reversible DWI lesion and 0.640±0.041 in final infarct DWI lesion (P<0.001). In 4 cases with hemorrhagic transformation, hemorrhagic transformation regions were 0.557±0.049 and non-hemorrhagic transformation regions were 0.762±0.042 (P<0.001). In addition, percentage DWI improvement was inversely correlated with DWI lesion volume at the time of hospitalization (r=-0.840) and onset-to-reperfusion time (r=-0.765), but no correlation was noted with patient age (r=-0.043) or the first NIHSS score (r=-0.277). CONCLUSIONS: The relative ADC ratio may be useful for predicting DWI reversibility and post-reperfusion hemorrhagic transformation, even in patients with an unknown time of onset.

Utility of MRI-based disproportionately enlarged subarachnoid space hydrocephalus scoring for predicting prognosis after surgery for idiopathic normal pressure hydrocephalus: clinical research.

OBJECTIVE The presence of disproportionately enlarged subarachnoid space hydrocephalus (DESH) on brain imaging is a recognized finding of idiopathic normal pressure hydrocephalus (iNPH), but the features of DESH can vary across patients. The aim of this study was to evaluate the utility of MRI-based DESH scoring for predicting prognosis after surgery. METHODS In this single-center, retrospective cohort study, the DESH score was determined by consensus between a group of neurosurgeons, neurologists, and a neuroradiologist based on the preoperative MRI findings of the patients with suspected iNPH. The DESH score was composed of the following 5 items, each scored from 0 to 2 (maximum score 10 points): ventriculomegaly, dilated sylvian fissures, tight high convexity, acute callosal angle, and focal sulcal dilation. The association between the DESH score and improvement of the scores on the modified Rankin Scale (mRS), iNPH Grading Scale (iNPHGS), Mini-Mental State Examination (MMSE), Trail Making Test-A (TMT-A), and Timed 3-Meter Up and Go Test (TUG-t) was examined. The primary end point was improvement in the mRS score at 1 year after surgery, and the secondary outcome measures were the iNPHGS, MMSE, TMT-A, and TUG-t scores at 1 year after surgery. Improvement was determined as improvement of 1 or more levels on mRS, ≥ 1 point on iNPHGS, ≥ 3 points on MMSE, a decrease of > 30% on TMT-A, and a decrease of > 10% on TUG-t. RESULTS The mean DESH score for the 50 patients (mean age 77.6 ± 5.9 years) reviewed in this study was 5.58 ± 2.01. The mean rate of change in the mRS score was -0.50 ± 0.93, indicating an inverse correlation between the DESH score and rate of change in the mRS score (r = -0.749). Patients who showed no improvement in mRS score tended to have a low DESH score as well as low preoperative MMSE and TMT-A scores. There were no differences in the areas of deep white matter hyperintensity and periventricular hyperintensity on the images between patients with and without an improved mRS score (15.6% vs 16.7%, respectively; p = 1.000). The DESH score did differ significantly between patients with and without improved scores on the iNPHGS (6.39 ± 1.76 vs 4.26 ± 1.69, respectively; p < 0.001), MMSE (6.63 ± 1.82 vs 5.09 ± 1.93; p = 0.010), TMT-A (6.32 ± 1.97 seconds vs 5.13 ± 1.93 seconds; p = 0.042), and TUG-t (6.48 ± 1.81 seconds vs 4.33 ± 1.59 seconds; p < 0.001). CONCLUSIONS MRI-based DESH scoring is useful for the prediction of neurological improvement and prognosis after surgery for iNPH.

Segmental Arterial Mediolysis Involving Both Vertebral and Middle Colic Arteries Leading to Subarachnoid and Intraperitoneal Hemorrhage.

BACKGROUND: Segmental arterial mediolysis (SAM) is not yet well known in the neurosurgical field, even though it has become an increasingly recognized pathology in arterial dissection. CASE DESCRIPTION: A case of SAM presented as subarachnoid hemorrhage (SAH) due to a dissecting aneurysm of the left intracranial vertebral artery (VA), which extended from the proximal VA union to the distal portion of the left posterior inferior cerebellar artery. The lesion was successfully embolized by an endovascular technique. However, subsequent intraperitoneal hemorrhage due to rupture of a fusiform aneurysm of the middle colic artery prompted surgical treatments. The features of the extirpated visceral vascular lesion were compatible with the diagnosis of SAM based on histopathologic examinations. CONCLUSIONS: It is very important that SAM is recognized as a systemic disease that affects the central nervous system, visceral arteries, and coronary arteries. The possibility of SAM should always be considered, particularly in patients with ruptured VA dissection-which is nowadays treated by endovascular techniques-since concomitantly involved visceral arteries may cause unexpected hemorrhagic complications other than SAH.

Extreme heterogeneous composition of the Paramecium caudatum macronuclear genomic DNA between hemoglobin and nucleosome assembly protein-1 genes.

The intergenic region between the hemoglobin (hb) and nucleosome assembly protein-1 (nap-1) genes in the Paramecium caudatum macronuclear genome was previously found to be heterogeneously composed. Cloning of this intergenic region from the macronuclear genomic DNA identified four unique DNA fragments of different sizes. Sequencing of the cloned fragments revealed extreme heterogeneity and characteristics of both internal eliminated sequence (IES) and imprecise internal deletion sequences (IIDSs) in the intergenic region. Missing sequences were an AT-rich and direct repeats existed in their boundaries. Southern blotting of the total genomic DNA and polymerase chain reaction (PCR) of the total genomic DNAs indicated that there exist a dozen DNA fragments of different sizes in this intergenic region. It is likely that the heterogeneity found in the P. caudatum macronuclear genome results from the variable removal of an intergenic region.

The presence of chimeric DNA consisting of 5' regions of the hemoglobin and nucleosome assembly protein-1 genes in Paramecium caudatum macronuclear genomic DNA.

We detected an unexpected small-sized DNA fragment during polymerase chain reaction (PCR) analysis of the heterogeneity of a macronuclear intergenic region of Paramecium caudatum. Southern blotting of total genomic DNA with the PCR product as a probe indicated that the small-sized DNA fragment constituted part of the macronuclear genome. Sequencing revealed that the PCR product was a chimeric DNA structure that may be generated by tail-to-tail fusion of the 5' region of the hemoglobin (hb) gene to most of the nucleosome assembly protein-1 (nap-1) gene. Short tandem repeats consisting of tetra- and tri-nucleotides exist at the putative cleavage sites in the hb and nap-1 genes, respectively. This feature differs from those found at the boundaries of TA-internal eliminated sequences in the P. aurelia complex and at transposable elements in other species. This suggests that the chimeric DNA is generated by a novel mechanism. Although the chimeric DNA contains the hb and nap-1 promoters, transcripts corresponding to the chimeric DNA were not detected by reverse transcription (RT)-PCR analysis during vegetative cell growth. Possible roles of chimeric DNA are discussed.

Alteration of developmental program in Paramecium by treatment with trichostatin a: a possible involvement of histone modification.

In the ciliate Paramecium caudatum, the somatic macronucleus for the next generation differentiates from a zygotic germinal micronucleus during conjugation. Subsequently, progeny are programmed to enter a sexually "immature" period, during which cells do not mate. This programming occurs at a critical period during the fifth cell cycle after conjugation. Here, we show that treatment with trichostatin A, a histone deacetylase inhibitor, leads to a partial recovery of mating reactivity in immature cells, suggesting that histone acetylation can affect the developmental program. In addition, immunostaining demonstrated that Lys 4 methylation of histone H3 was absent from or present at an undetectable level in the nascent macronucleus during the first cell cycle after conjugation. The methylation level gradually increased in proportion to de novo DNA synthesis, until the new macronucleus reached the maximum level of methylation, concomitant with its full maturation. A link between gene expression and Lys 4 methylation is indirectly supported by the observation that a transcriptionally active gene was enriched by chromatin immunoprecipitation with an antibody directed against methyl-Lys 4 H3, whereas a silent gene was not. These results provide evidence that histone modification plays a key role in the regulation of gene expression and the developmental programming that determine sexual immaturity after conjugation.

Selection of the germinal micronucleus in Paramecium caudatum: nuclear division and nuclear death.

Each cell of Paramecium caudatum has a germinal micronucleus. When a bi-micronucleate state was created artificially by micronuclear transplantation, both micronuclei divided for at least 2 cell cycles after nuclear transplantation. However, this bi-micronucleate state was unstable and reduced to a uni-micronucleate state after several fissions. Although the number of micronuclei was usually 1 during the vegetative phase, 4 presumptive micronuclei differentiated after conjugation. At the first post-conjugational fission, only 1 of the 4 micronuclei divided, indicating that there is tight regulation of micronuclear number in exconjugants. Micronuclei that did not divide at the first post-conjugational fission may persist through the first and second post-conjugational cell cycles. The decision to divide appears to be separate from the decision to degenerate, as evidenced by division of a remaining micronucleus upon removal of the dividing micronucleus at the first division. Degeneration of micronuclei in exconjugants differs from that of haploid nuclei after meiosis. Nutritional state affected micronuclear degeneration. Under well-fed conditions, the micronuclei destined to degenerate lost the ability to divide earlier than after starvation treatment, suggesting that micronuclear degeneration is an "apoptotic" phenomenon, probably under the control of the new macronuclei (macronuclear anlagen).

Delayed degradation of parental macronuclear DNA in programmed nuclear death of Paramecium caudatum.

In the ciliated protozoan Paramecium caudatum, a parental macronucleus that is fragmented into some 40-50 pieces during conjugation does not degenerate immediately, but persists until the eighth cell cycle after conjugation. Here we demonstrate that the initiation of the parental macronuclear degeneration occurs at about the fifth cell cycle. The size of parental macronuclear fragments continued to increase between the first and fourth cell cycle, but gradually decreased thereafter. By contrast, a new macronucleus grew and reached a maximum size by the fourth cell cycle, suggesting that the new macronucleus matured by that stage. Southern blot analysis revealed that parental macronuclear DNA was degraded at about the fifth cell cycle. The degradation was supported by acridine orange staining, indicating degeneration of the macronuclear fragments. Prior to the degradation, the fragments once attached to the new macronucleus were subsequently liberated from it. These observations lead us to conclude that once a new macronucleus has been fully formed by the fourth cell cycle, the parental macronuclear fragments are destined to degenerate, probably through direction by new macronucleus. Considering the long persistence of the parental macronucleus during the early cell cycles after conjugation, the macronuclear fragments might function in the maturation of the imperfect new macronucleus. Two possible functions, a gene dosage compensation and adjustment of ploidy level, are discussed.

Interactions between newly developed macronuclei and maternal macronuclei in sexually immature multinucleate exconjugants of Paramecium caudatum.

The macronucleus of Paramecium caudatum controls most cellular activities, including sexual immaturity after conjugation. Exconjugant cells have two macronuclear forms: (1) fragments of the maternal macronucleus, and (2) the new macronuclei that develop from the division products of a fertilization micronucleus. The fragments are distributed into daughter cells without nuclear division and persist for at least eight cell cycles after conjugation. Conjugation between heterokaryons revealed that the fragmented maternal macronuclei continued to express genetic information for up to eight cell cycles. When the newly developed macronucleus was removed artificially within four cell cycles after conjugation, the clones regenerated the macronuclear fragments (macronuclear regeneration; MR) and showed mating reactivity, because they were sexually mature. However, when the new macronucleus was removed during later stages, many MR clones did not show mating reactivity. In some extreme cases, immaturity continued for more than 50 fissions after conjugation, as seen with normal clones that had new macronuclei derived from a fertilization micronucleus. These results indicate that the immaturity determined by the new macronucleus is not annulled by the regenerated maternal macronucleus. Mature macronuclear fragments may be "reprogrammed" in the presence of the new macronucleus, resulting in their expression of "immaturity."

Characterization of the spasmin 1 gene in Zoothamnium arbuscula strain Kawagoe (protozoa, ciliophora) and its relation to other spasmins and centrins.

Zoothamnium arbuscula strain Kawagoe is a giant sessile peritrich ciliated protozoa that possesses a contractile organelle called a spasmoneme. We report here on the molecular characterization and provide an opportunity to discuss the evolutionary relationships of the Z. arbuscula spasmin; spasmins belong to the calmodulin superfamily and are the major components of spasmoneme filaments. We analysed and obtained the whole sequence of the spasmin 1 gene and a partial sequence of the spasmin 2 gene. It is surprising that the sequence of spasmin 1 does not contain introns and encodes an open reading frame of 531 bp. It predicts a product of 177 amino acids with a calculated molecular mass of 19659 Da and a pI of 4.68. The amino acid sequence has two putative calcium-binding domains. One of them is a functional domain, as defined by the EF-hand consensus. The varieties of spasmins were revealed by comparison with amino acid components and molecular relationships of spasmin 1 protein and other spasmins. A comparison of the amino acid sequence between the Z. arbuscula spasmin and known centrins indicates that spasmins have a one residue deletion in the EF-hand domain-2 and four residue insertions in domain-4, as does the Vorticella spasmin. However, there are large variations in the amino acid sequence at domain-4 within spasmin 1, spasmin 2 and the Vorticella spasmin.

Phylogenetic relationships between Vorticella convallaria and other species inferred from small subunit rRNA gene sequences.

Vorticellid ciliates generally dwell in freshwater. In nature, the species have up until now been identified by comparison with previous descriptions. It is difficult to identify between species of the genus Vorticella, because the morphological markers of vorticellid ciliates described in reports are limited and variable. Unfortunately, culturing them has only succeeded with certain species such as Vorticella convallaria, but many others have been impossible to culture. To find out whether the sequence of a small subunit rRNA gene was an appropriate marker to identify vorticellid ciliates, the gene was aligned and compared. Finding a new convenient method will contribute to research on vorticellid ciliates. In strains of V. convallaria, classified morphologically, some varieties of the SSrRNA gene sequences were recognized, but there were large variations within the same species. According to the phylogenetic tree, these strains are closely related. However, the difference was not as big as between Vorticella and Carchesium. In addition, Carchesium constructed a distinct clade from the genus Vorticella and Epistylis. These results show the possibility that the SSrRNA gene is one of the important markers to identify species of Vorticella. This study is first to approach and clarify the complicated taxa in the genus Vorticella.

Microtubules mediate germ-nuclear behavior after meiosis in conjugation of Paramecium caudatum.

Microtubule dynamics in Paramecium caudatum were investigated with an anti-alpha-tubulin antibody and a microinjection technique to determine the function of microtubules on micronuclear behavior during conjugation. After meiosis, all four haploid micronuclei were connected by microtubular filaments to the paroral region and moved close to this region. This nuclear movement was micronucleus-specific, because some small macronuclear fragments transplanted from exconjugants never moved to the region. Only one of the four germ nuclei moved into the paroral cone and was covered by microtubule assembly (the so-called first assembly of microtubules, AM-I). This nucleus survived there, while the other three not in this region degenerated. The movement of germ nucleus was inhibited by the injection of the anti-alpha-tubulin antibody. The surviving germ nucleus divided once and produced a migratory pronucleus and a stationary pronucleus. Prior to the reciprocal exchange of the migratory nuclei, microtubules assembled around the migratory pronuclei again (the so-called second assembly of microtubules, AM-II). Then, the migratory pronucleus moved into the partner cell and fused with the stationary pronucleus. Thus, microtubules appear to be indispensable for nuclear behavior: they enable migration of postmeiotic nuclei to the paroral region and they permit the survival of the nucleus at the paroral cone.

Effects of K+ and the K+ Ionophore Valinomycin on the Post-Conjugational Nuclear Differentiation of Paramecium caudatum: (determination/macronucleus/Paramecium/potassium/valinomycin).

For determination of the effect of K+ on macro- and micronuclear differentiation Paramecium caudatum exconjugants were transferred to medium with various concentrations of Valinomycin and/or K+ at the critical stage of nuclear differentiation. The differentiation was not disturbed by transfer to medium containing 1.5 mM to 50 mM KCl. Injection of KCl solution at the critical stage also did not affect differentiation of the macronucleus appreciably. But change of the KCl concentration in the medium at the critical stage interrupted of normal development of the macronucleus. Macro- and micronuclear differentiations after conjugation are known to be determined by the antero-posterior localization of postzygotic micronuclei. This nuclear localization is achieved by elongation of mitotic spindles and marked shortening of the cell length at the time of micronuclear division. Successive measurements of cell length at 25°C showed that cells began to shorten 1.5 hr after mating-pair separation, reaching to half the initial length about 2.5 hr after the separation, and then returning to recover their initial length within about 50 min. In a solution of K+ (50 mM) plus Valinomycin (1µg/ml or more), cell shortening was inhibited. It is not known whether elongation of mitotic spindles at the time of critical nuclear division was disordered by this treatment, but the macronuclear anlagen developed in the treated cells. Thus shortening in the cell length is not indispensable for nuclear differentiation.

Nuclear Differentiation in Exconjugants of Paramecium caudatum: Role of Nuclear Division in Differetiation: (conjugation/nuclear differentiation/nuclear division/nuclear transplantation/Paramecium).

It has been known that, immediately after the third division of fertilization nucleus (synkaryon), nuclei localized near the posterior region of exconjugant are to be macronuclear anlagen and those near the anterior region are to be presumptive micronuclei in Paramecium caudatum. One of such posterior nuclei was transplanted into amicronucleate cell at vegetative phase in this work. The implanted nuclei were able to divide at every fission. Their DNA content was nearly equal to or less than ordinary micronuclei during vegetative phase. When conjugation was induced between clones obtained and amicronucleates, macronuclear anlagen developed from the division products of implanted nuclei and thereafter derivative caryonides were true to the marker gene of implanted nuclei. The results indicate that there was no intrinsic difference between nuclei localized anteriorly and those situated posteriorly in exconjugant. Differentiation of nuclei into macronucleus may be irreversible at the stage of anteroposterior localization of the nuclei. The role of nuclear division in differentiation may be only to transport the daughter nuclei into the cytoplasm/cortex differentiated anteroposteriorly.